Genetic landscape of hereditary spastic paraplegias in the Korean population

Hereditary spastic paraplegia (HSP) is a genetically neurodegenerative disorder with limited epidemiological data in Korea. This study aimed to characterize the genetic landscape of HSP in a large Korean cohort. We analyzed 657 patients with suspected HSP using Sanger sequencing and a targeted next-generation sequencing (NGS) panel covering 54 HSP-related genes. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, and copy number variations (CNVs) were detected using in-house methods and multiplex ligation-dependent probe amplification. Pathogenic or likely pathogenic variants were identified in 121 patients (18%), with SPAST (83%) and ATL1 (6%) being the most frequently mutated genes. Notably, 5% of SPAST mutations were CNVs, underscoring the importance of CNV detection. Among the identified variants, 23 novel mutations were discovered, primarily in SPAST (19), REEP1 (3), and SACS (1), expanding the mutational spectrum of HSP. The diagnostic yield was higher with NGS (25%) compared to Sanger sequencing (16%), reflecting the panel's broader gene coverage. This study highlights the predominance of SPAST and ATL1 mutations in Korean HSP patients and emphasizes the utility of targeted NGS panels, particularly for detecting CNVs and novel variants. Despite these advances, the majority of cases remain unresolved, suggesting the need for broader sequencing approaches to uncover additional genetic factors. These findings provide a foundation for improved diagnostic strategies and personalized treatment in HSP.